This project is designed to investigate the effects of intravenous transplantation of bone marrow stromal cells on brain after traumatic brain injury. Traumatic brain injury (TBI) is an important cause of human morbidity and as many as 50,000 Americans are killed and an equal number are disabled by head trauma each year. Currently, treatment of TBI primarily consists of evacuating mass lesions and providing an optimal milieu for the brain to recover. Preliminary data indicate that bone marrow stromal cells (MSCs) induce functional benefit in animals subjected to TBI. In this application, functional response of young male rats and mice subjected to TBI after intravenous (i.v.) administration of MSCs will be measured, and effective doses of MSCs will be determined. A battery of functional outcome measurements will be performed to test for enhanced recovery resulting from MSC treatment (Specific Aim 1). We propose, that therapeutic benefit from MSC treatment of TBI derives from the production of growth factors in brain by the interaction of MSCs with injured brain. To support this hypothesis, growth factors produced in brain in response to different doses of MSCs will be measured for different degrees of injury in rats, and a temporal profile of growth factor production will be measured and related to functional response (Specific Aim 2). The MSC enhancement of these growth factors may affect endogenous cell proliferation and their phenotype in the subventdcular zone (SVZ) and the hippocampal formation in animals subjected to TBI. Of basic interest, is the fate of the MSCs in brain after TBI, whether they are modified and express over the long-term markers of other cell types. To address these questions, the temporal profile for cell phenotype of exogenous MSCs in injured brain and endogenous cell proliferation and phenotype in the SVZ and hippocampal formation will be measured in rats subjected to TBI and treated with MSCs. Cell phenotype and cell proliferation measurements will also be performed in mice receiving MSCs from transgenic GFP mice. If intravenous transplantation of marrow stromal cells succeeds in improving functional outcome, a new avenue will be opened for further development of therapeutic interventions to improve outcome after traumatic brain injury.